Download Eur J Clin Pharmacol (1986) 31 [Suppl]: 29

European Journal of
Clinical Pharmacology
Eur J Clin Pharmacol (1986) 31 [Suppl]: 29-34
© Springer-Verlag 1986
Torasemide, a New Potent Diuretic
Double-Blind Comparison with Furosemide
J. Broekhuysen1, F. Deger2, J. Douchamps2, H. Ducarne2 and A. Herchuelz2,3
1
Institut de Pharmacologie et d'Investigations Biomédicales, Charleroi
Unité de Pharmacologie Clinique, Centre Hospitalier Universitaire de Montigny-le-Tilleul, Montigny-le-Tilleul and
3 Laboratoire de Pharmacologie, Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium
2
Summary. The pharmacodynamic effects of torasemide, a new potent loop diuretic, were compared
with those of furosemide in a double blind controlled study in 18 hypertensive patients with oedema of various origins. Given orally for 5 days, torasemide was clinically very effective and well tolerated.
On a weight basis, the diuretic, natriuretic and
chloruretic effects of torasemide were about 8-times
greater than those of furosemide. However, the kaliuretic effect of torasemide was only 3-times greater
than that of furosemide, suggesting that torasemide
is more potassium sparing than furosemide.
Torasemide displayed a rapid onset of action,
similar to that of furosemide but had a longer diuretic effect without any rebound phenomenon. Torasemide and furosemide did not effect creatinine clearance or uric acid excretion.
Both furosemide and torasemide lowered systolic
blood pressure but the effect of torasemide was more
marked than that of furosemide. In this group of
aged and hypertensive patients with oedema, the
pharmacokinetics of torasemide was comparable to
that reported in young healthy volunteers, and were
similar on the first and fifth days of treatment.
The long duration of action and the potassium
sparing effect of torasemide compared to furosemide
are promising features of this new loop diuretic in
the treatment of oedema and hypertension.
piretanide (Delarge et al. 1978). In animals (dogs and
rats) and human volunteers, it displays a pharmacological profile comparable to that of furosemide
(Ghys et al. Lesne 1982). In animals, torasemide is 5to 10-times more potent than furosemide on a weight
basis. In healthy volunteers it has a higher bioavailability and longer biological half life than furosemide, with a longer duration of action (Lesne et al.
1982).
The aim of the present work was to compare the
diuretic effects of torasemide and furosemide given
for 5 days to aged patient with hypertension and oedema of various origins.
Material and Methods
Patients
Eighteen oedematous patients (6 men and 12 women) participated in the study. Their underlying diseases were congestive heart failure (11 cases), cor
pulmonale (3 cases) and hepatic cirrhosis (4 cases).
Their ages ranged from 56 to 87 years. There was no
difference between the treatment groups with respect
to age, body weight and underlying disease (Table 1).
Key words: torasemide, hypertension; diuretic potency, furosemide, pharmacodynamics
Torasemide is a new loop diuretic with a pyridinesulphonylurea-structure (Fig. 1) different from common loop diuretics, like furosemide, bumetanide or
Fig. 1. Structural formula of torasemide. isopropyl-1methyl-3 phenylamino-4 pyridil-3 sulphonyl- 3-urea
J. Broekhuysen et al.: Torasemide, a New Diuretic
30
Table 1. Characteristics of the study population
Daily dosage
Patients (n)
Age (years)
Body weight
(kg)
Diagnosis
Heart failure
Hepatic cirrhosis
Supine blood
pressure
systolic
(mmHg)
diastolic
(mmHg)
Torasemide Torasemide
10 mg
20 mg
Furosemide p
40 mg
6
71 ±3
74.3 ± 3.2
6
8 1 ±2
65.3± 6.7
6
75 ± 5
57.8 ± 3.0
4
2
5
1
5
1
178 ±8
187 ±15
195 ±15
ns
100 +4
94 ± 7
120 ± 8
ns
ns
ns
Before entering the study, patients were submitted to
a thorough medical examination including case history, physical examination, chest X-ray, ECG, haematology, blood chemistry and urinalysis. All patients were given a constant sodium and potassium
diet.
When necessary, previous diuretic therapy was
withdrawn at least 3 days before the beginning of the
study while concomitant medication (e.g. cardiac
glycosides) was kept unchanged. Informed consent
was obtained from each patient and the protocol was
cleared by the Ethical Committee of the hospital.
Treatment and Clinical Regimen
The study was conducted double-blind and patients
were randomly assigned to either l0 mg torasemide,
20 mg torasemide or 40 mg furosemide. The diuretics
were given orally as a single morning dose during a
five-day period, which was preceded and followed
by two-day control periods. During control and
treatment periods, blood samples were taken each
morning for the measurement of serum ions, urea,
creatinine and uric acid.
During control periods, urine was collected over
24-h intervals. During the treatment period, urine
was collected from 0 to 4,4 to 8,8 to 12 and 12 to 24 h
after drug intake. On Days 1 and 5 of the treatment
period, additional blood samples were taken for the
assay of torasemide in plasma.
Patients were weighed each morning and blood
pressure (supine and erect) was measured twice daily.
Assay of Torasemide
Torasemide was assayed by reverse phase (Chrompack RP8) HPLC, after extraction by ethyl acetate of
plasma buffered at pH4.2. Elution was brought
about by a multistep gradient of acetonitrile (30 to
70%) in 0.05 M acetate buffer pH 4.2, and was monitored at 290 nm. The internal standard was JDL-424,
structurally related to torasemide.
Urine samples were similarly assayed. Calibration curves were linear from 0.1 to 20 mg/1. The limit
of sensitivity of the assay was 0.02 mg/1 in plasma
and 0,05 mg/1 in urine.
Fig. 2. Relative urinary volume (upper panel) and clearance of
Na+ (middle panel) and Cl- flower panel) after torasemide l0 mg
and 20 mg and furosemide 40 mg. Mean ( ± SEM) changes are expressed relative to the off-treatment baseline value (taken as 1;
mean of the two pre-treatment days and the two post-treatment
days). For control periods, the figures illustrated are the mean values during the off-treatment-period. Mean control values for urinary volume were 0.77 ± 0.14, 1.14±0.21 and 0.96±0.161/24h,
respectively. Mean (± SEM) control values for Na+ and Clclearance are illustrated in Table 2
Statistical Analysis
All data are expressed as mean ± SEM. Differences
between treatment regimens were evaluated by comparing the changes from baseline levels (the two days
before and after treatment) induced by each drug,
employing multiple linear regression and/or vari
J. Broekhuysen et al.: Torasemide, a New Diuretic
31
Fig. 3. Fractional urinary volume on the first day of
treatment after diuretic administration (time 0).
Mean values (±SEM) are expressed relative to
mean off-treatment baseline value, as illustrated by
the dotted line
Table 2. Clearances of sodium, chloride, potassium, calcium, phosphate, creatinine, and urea during control and treatment periods
(mean±SEM)
Torasemide 10 mg
Sodium
Chloride
Potassium
Calcium
Phosphate
Creatinine
Urea
Furosemide 40 mg
Torasemide 20 mg
Control
Treatment
Control
Treatment
Control
Treatment
0.10 ±0.05
0.1 5 ±0.07
6.56 ±0.64
0.35 ± 0.14
8.18 ± 1.10
55.32 ± 5.70
21.48 ± 2.56
0.29 ± 0.05
0.58 ±0.07
9.82 ±1.14
0.63 ±0.11
9.09 ± 1.14
54.34 ± 7.39
23.94 ± 4.38
0.09 ±0.03
0.11±0.05
5.55 ± 0.29
0.10 ± 0.29
6.19 ±1.77
36.38 ± 6.00
15.90 ± 3.24
0.55 ±0.10
0.89 ±0.14
12.85 ±1.60
0.44 ±0.06
10.43 + 2.81
44.76 ±6.32
14.89 ± 2.42
0.13 ± 0.02
0.18 ± 0.03
5.98 ± 1.54
0.25 ± 0.07
5.76 ± 139
30.88 ± 4.97
16.28 ±4.56
0.40 ±0.05
0.65 ±0.07
9.22 ±1.88
0.40 ±0.08
6.90 ±1.58
31.03 ± 3.45
15.48 ± 3.87
ance analysis. Variance analysis showed that there
was no significant difference between the three
groups of patients with respect to laboratory data
collected during the control periods (p > 0.5).
furosemide 40 mg induced mean weight losses of
2.9 kg, 2.8 kg and 2.3 kg, respectively.
Results
The effects of torasemide and furosemide on ion
clearance are illustrated in Table 2 and Fig.2 and 4.
All three treatments significantly increased the clearance of Na+, C1-, K+, Ca2+and PO34- (p <0.005 or
less). As judged over the 5 days of treatment, the
mean increase in the relative clearance of Na+ was
about 2- and 4-times higher with torasemide l0 mg
and 20 mg, respectively, than after 40 mg furosemide
(p< 0.025). A similar picture was observed for Clclearance (p< 0.0025).
After torasemide 10 mg, the increase in K+ clearance was slightly lower, while it was 1.4-times higher
after 20 mg torasemide than furosemide (p< 0.001).
During the first 4 hours of the first day of treatment,
the urinary Na+/K+ ratio averaged 3.4 ±0.7 (n = 6),
4.6 ± 0.9 (n = 5) and 3.5 ± 0.7 (n = 6) after torasemide
l0 mg, torasemide 20 mg and furosemide 40 mg, respectively. Thus, on a weight basis, torasemide was
8-times more natriuretic and chloruretic than furosemide, but it was only about 3-times more kaliuretic.
The increases in Ca2+ and PO34- clearance were sig-
Urinary Volume and Body Weight
Daily urinary volume increased with all three treatments (p < 0.05; Fig. 2 upper panel), the increase being more marked with torasemide than with furosemide (p < 0.015). Thus, torasemide 10 mg and 20 mg,
and furosemide 40 mg. increased mean daily diuresis
by 95%, 114% and 62%, respectively. In all groups,
the diuresis peaked during the first period of urine
collection (0-4 h) and declined rapidly thereafter.
The decline was slower after torasemide than furosemide (p < 0.05). The fractional diuresis observed on
the first day of treatment after torasemide and furosemide is shown in Fig. 3. The urinary volume exceeded the mean baseline value during all collection
periods after torasemide. It was depressed below
baseline during the second (4-8 h) and third periods
(8-12 h) of collection after furosemide (Fig. 3). During treatment, torasemide 10 mg and 20 mg and
Urinary Excretion of Ions, Urea, Creatinine
and Uric Acid
32
nificantly higher after both doses of torasemide than
after furosemide (p< 0.025). Neither drug significantly increased the clearance of urea or of creatinine (p >0.05). They also failed to affect uric acid
excretion (p > 0.05).
J. Broekhuysen et al.: Torasemide, a New Diuretic
Clinical Symptoms and Side-Effects
All patients showed clinical improvement with relief
of symptoms. None of the three drug treatments gave
rise to side-effects, except for an orthostatic hypotensive episode in two patients, one on furosemide, and
one on torasemide 20 mg.
In one patient on furosemide, clinical signs of dehydration required drug withdrawal on the 4th day
of treatment.
No treatment-related change in blood chemistry
or hematology was noticed with either torasemide
treatment. In the furosemide group, blood haematocrit, red cell count and haemoglobin decreased by
about 10% (p < 0.05). Neither torasemide nor furosemide significantly decreased diastolic blood pressure. Both drugs decreased erect and supine systolic
blood pressure (p < 0.05), but the drop in pressure
was more marked after torasemide than furosemide
(Fig. 5) in the morning (p < 0.001) and in the evening
(p<0.02).
None of the patients required K+ supplements
except for two on furosemide in whom the plasma
K+ fell below 3 mmol/1 (in one patient on the 4th
day of treatment, and in the other on the second
post-treatment day).
Pharmacokinetics of Torasemide
Fig. 4. Relative clearance of Ca2+ (upper panel), PO34- (middle
panel) and K+ (lower panel) with torasemide 10 mg and 20 mg and
furosemide 40 mg. Mean (±SEM) changes are expressed as in
Fig. 2. The control values are given in Table 2
Comparable pharmacokinetic profiles were observed on Days 1 and 5, the ratio of the AUC (0 to 8
or 12 h) on Day l to that on Day 5 being 0.87
±0.08 (n = 10). Hence, the data from the two days
were pooled.
Mean plasma torasemide concentrations after intake of 10 mg and 20 mg are illustrated in Fig. 6. Torasemide was usually detected in plasma collected
0.5 h after dosing. The time to peak ranged from 0.5
Fig. 5. Mean systolic and diastolic blood pressures
measured in the morning on the day before starting
and the day after ending treatment with torasemide
10 mg and 20 mg and furosemide 40 mg. Blood pressure was measured in erect (Δ) and supine(O) positions
J. Broekhuysen et al.: Torasemide, a New Diuretic
33
Fig. 6. Plasma torasemide concentration
versus time following single doses of
10 mg (•....... •) and 20 mg (•
•);
mean ( ± SEM) values on Days 1 and 5 of
treatment
Table 3. Pharmacokinetic parameters of torasemide
cmax
Torasemide
10 mg
Torasemide
20 mg
(mg/1
1.1 ±0.2
3.7 ±0.9
1.25 ±0.25
AUC(0-12) t½
(mg-h-1-1) (h)
5.5 ±1.6
3.8 ±0.4
0.83 ±0.11
10.2 ±2.4
tmax
(h)
3.8 ±0.5
to 2 h (mean 1 h). The area under the plasma concentration curve (0-12 h) reached a mean value of
5.5mg.h.1-1 after 10mg and was almost twice as
large after 20 mg, i. e. 10.2 mg • h • 1-1.
The decline with time of plasma torasemide followed single or multiexponential kinetics. The pharmacokinetic parameters of torasemide are listed in
Table 3. The elimination rate constant and corresponding half-life did not differ from that previously
reported in young healthy volunteers (Lesne et al.
1982).
Discussion
Since there was no significant difference between the
three groups of patients with respect to age, body
weight, blood pressure, cause of underlying disease
and laboratory data collected before the start of the
study, the efficacy and potency of torasemide and furosemide could be adequately compared.
Torasemide was comparable in the onset and
peak of action to furosemide, the action of both
drugs culminating during the first 4h following their
administration. However, the action of torasemide
appeared to last longer than that of furosemide as
judged from the urinary volumes observed during
the 5 days of treatment. Furthermore, unlike furosemide no fall in diuresis below baseline was observed
in the 4th to 12th hour period after torasemide on the
first day of treatment, despite a higher diuresis with
torasemide than with furosemide during the first period of urine collection (0-4 h).
Over the complete experimental period (5 days),
10 mg and 20 mg torasemide were respectively 2- and
4-times more effective than 40 mg furosemide on the
relative clearance of sodium and chloride. Thus, torasemide appears to be 8-times more potent than furosemide on a weight basis. However, the comparative potency of torasemide over that of furosemide
on the relative clearance of K+ (about 3-fold) was
lower than on the relative clearances of Na and Cl-,
indicating that torasemide is more K+-sparing than
furosemide.
Both drugs were generally well tolerated, except
that furosemide had to be withdrawn in one patient
for orthostatic hypotension and hypokalaemia. Even
at the highest dose, torasemide did not affect the
clearance of creatinine. It significantly lowered systolic blood pressure, an effect which warrants further
investigation.
Overall, torasemide is a potent diuretic which
may have a longer lasting effect than furosemide.
The drug was well tolerated and clinically efficient in
this group of 18 oedematous patients. It appears to
be more K-sparing than furosemide.
Acknowledgements. We are indebted to Ms. E. Freschi and E. Godart of the nursing staff for their skilful
34
J. Broekhuysen et al.: Torasemide, a New Diuretic
assistance, to A. Bouckaert, Department of Epidemiology, Universite Catholique de Louvain, for statistical analysis and to C. De Weerdt for secretarial
help.
Lesne M, Clerckx-Braun F, Duhoux P, van Ypersele de Strihou
Ch (1982) Pharmacokinetic study of torasemide in humans:An
overview of its diuretic effect. Int J Clin Pharmacol Ther Toxicol 20: 382-387
References
Received: August 15,1985
accepted: October 16,1985
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"high ceiling", dérivés de l'alkyl-1 [(phenylamino-4 pyridyl-3)
sulfonyl]-3 urée. Ann Pharm Fr 36: 369-380
Ghys A, Denef J, de Suray JM, Gerin M, Georges A, Delarge J,
Willems J (1985) Pharmacological properties of the new potent
diuretic torasemide in rats and dogs. Arzneimittelforsch/Drug
Res 35:1520-1526
A. Herchuelz
Unité de Pharmacologie Clinique
Centre Hospitalier Universitaire de Montigny-le-Tilleul
Route de Gozée, 706
B-6110 Montigny-le-Tilleul, Belgium